A randomized controlled proof-of-concept trial of digoxin and furosemide in adults with cutaneous warts.

BACKGROUND: Topical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts. OBJECTIVES: To assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT. METHODS: Treatment with ICVT was assessed for efficacy, safety and tolerability in a single- centre, randomized, double-blind, placebo-controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed-model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643. RESULTS: Wart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (-3·0 mm, 95% confidence interval -4·9 to -1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (-94%, 95% confidence interval -100 to -19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts. CONCLUSIONS: This study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.

Developing and validating the Cutaneous WARTS (CWARTS) diagnostic tool: a novel clinical assessment and classification system for cutaneous warts.

BACKGROUND: The clinical appearance of cutaneous warts is highly variable and not standardized. OBJECTIVES: To develop and validate a reproducible clinical tool for the standardized assessment of cutaneous warts to distinguish these lesions accurately. METHODS: Nine morphological characteristics were defined and validated regarding intra- and interobserver agreement. Based on literature and semistructured interviews, a systematic dichotomous assessment tool, the Cutaneous WARTS (CWARTS) diagnostic tool was developed. The validation consisted of two independent parts performed with photographs from the recent WARTS-2 trial. In part A, the CWARTS diagnostic tool was tested by 28 experienced physicians who assessed photographs of 10 different warts to investigate interobserver concordance. In part B, morphological characteristics were validated by masked and independent scoring of 299 photographs by six different observers. Part B also entailed reassessment of the photographs after at least 1 week. The primary outcome measurement was the intraclass correlation coefficient (ICC). RESULTS: Presence of black dots (capillary thrombosis) had the greatest ICC (0·85) for interobserver agreement in part A, followed by arrangement (0·65), presence of border erythema (0·64) and sharpness of the border (0·60). In part B, results were similar for interobserver agreement with presence of black dots having the highest ICC (0·68), followed by border erythema (0·64), arrangement (0·58) and colour (0·55). For intraobserver agreement, presence of black dots had the highest agreement (0·70), followed by presence of border erythema (0·694) and colour (0·59). CONCLUSIONS: Wart phenotype can be reliably assessed using the CWARTS diagnostic tool.

Morphological characteristics and human papillomavirus genotype predict the treatment response in cutaneous warts.

BACKGROUND: Cutaneous warts have a cure rate after therapy of no more than approximately 50%. Recently, we developed and validated a standard assessment tool for warts (Cutaneous WARTS diagnostic tool, CWARTS) based on phenotypical characteristics. OBJECTIVES: To assess whether patient and morphological wart characteristics predict the human papillomavirus (HPV) type in a specific wart and whether these characteristics as well as the HPV type predict a favourable treatment response. METHODS: Photographs were used to score nine morphological wart characteristics using the newly developed CWARTS tool. Genotyping of 23 wart-associated HPV types was performed using the hyperkeratotic skin lesion-polymerase chain reaction/multiplex genotyping assay. The results were correlated with a favourable response to treatment with monochloroacetic acid, cryotherapy or a combination of cryotherapy and salicylic acid. Odds ratios were calculated using logistic regression in a generalized estimating equations model. RESULTS: Black dots (capillary thrombosis) strongly predicted the presence of any HPV type in a wart. From all characteristics tested, the HPV type most strongly predicted the treatment response when the warts were treated with monochloroacetic acid or a combination of cryotherapy and salicylic acid with a significantly decreased treatment response if the warts contained HPVs of the alpha genus (HPV2, HPV27 or HPV57). When cryotherapy alone was used for common warts, HPV type did not play a role, but cryotherapy was less effective in the presence of callus and when the wart was located deeper in the skin. CONCLUSIONS: Morphological characteristics of the warts and the HPV genotype influence treatment outcome and thus potentially influence future treatment decisions for common and plantar warts.

Topical ionic contra-viral therapy comprised of digoxin and furosemide as a potential novel treatment approach for common warts.

BACKGROUND: DNA viruses such as HPV rely on K+ influx for replication. Both digoxin and furosemide inhibit the K+ influx by interacting with cell membrane ion co-transporters (Na+ /K+ -ATPase and Na+ -K+ -2Cl- co-transporter-1, respectively). We therefore hypothesized that these two compounds in a topical formulation may be valuable in the treatment of HPV-induced warts. This new approach is called Ionic Contra-Viral Therapy (ICVT). OBJECTIVE: To evaluate systemic exposure, safety and tolerability of ICVT with a combination of furosemide and digoxin after repeated topical application in subjects with common warts. Furthermore, we aimed to evaluate pharmacodynamics effects of ICVT. METHODS: Twelve healthy subjects with at least four common warts on their hands were included in the study and treated with a fixed dose of 980 mg topical gel containing 0.125% (w/w) digoxin and 0.125% (w/w) furosemide for 7 consecutive days on their lower back to assess safety and systemic exposure. Two warts were treated with 10 mg each and two served as negative controls to obtain preliminary evidence of treatment effect. RESULTS: ICVT was well tolerated topically, and there was no evidence of systemic exposure of digoxin or furosemide. There were no clinical relevant safety findings and no serious adverse events (SAEs). A rapid and statistically significant reduction in diameter, height and volume of the warts was already observed at day 14. CONCLUSION: ICVT was found to be safe for administration to humans and 7 days of active treatment showed a statistical significant wart reduction compared to untreated control lesions, clearly indicating pharmacological activity.

Dorsal capsuloplasty for dorsal instability of the distal ulna.

Background Dorsal instability of the distal ulna can lead to chronic wrist pain and loss of function. Structural changes to the dorsal radioulnar ligaments (DRUL) of the triangular fibrocartilage complex (TFCC) and the dorsal capsule around the ulnar head with or without foveal detachment can lead to volar subluxation of the distal radius e.g., dorsal instability of the distal ulna. Purpose Is to evaluate the post-operative results of reinstituting distal radioulnar joint (DRUJ) stability through reefing of the dorsal capsule and dorsal radioulnar ligaments, with and without a foveal reattachment of the TFCC. Methods A total of 37 patients were included in this retrospective study. Diagnosis and treatment was based strictly on dry wrist arthroscopy. In 17 patients isolated reefing of the DRUL and their collateral tissue extension was performed. In 20 patients an additional foveal reinsertion was performed. Postoperative results were evaluated with the DASH questionnaire, VAS scores, grip strength and range of motion. These findings were extrapolated in the Mayo wrist score. The two subgroups were compared. Results Mayo wrist scores of the whole population had a mean of 73. There was no difference between the group that was treated with reefing of the DRUL only and the group that was treated with a combined foveal reinsertion. Conclusion This relatively simple 'dorsal reefing' procedure, with foveal reinsertion when indicated, is a reliable method to restore volar-dorsal DRUJ stability with a significant decrease in pain sensation, good DASH scores and restoration of functional grip strength and ROM. Type of Study/Level of Evidence Therapeutic, Level IV.

The pre-operative stratification of patients with colorectal liver metastases: computed tomography arterial portography (CTAP) has no added value.

AIMS: The purpose of this study was to determine if Computed Tomography Arterial Portography (CTAP) has additional value to Contrast Enhanced helical CT (CE-CT) in selecting patients for hepatic surgery or Isolated Hepatic Perfusion/systemic chemotherapy. MATERIALS AND METHODS: Forty-one patients were included. All CT's were performed in the normal pre-operative work-up of patients with liver metastases in our regular clinical setting and reviewed blinded by a radiologist. For CE-CT and CTAP the number, size (largest diameter) and location of all suspected malignant liver lesions were recorded. The favourable treatment option was determined based on the results of CE-CT and CTAP independently. The therapeutic decision based on CE-CT and CTAP was compared with the definite treatment. For all patients with recorded findings during surgery, consisting of intra-operative ultrasound, liver palpation and histology a standard of reference for lesion detection was available. For these patients detection rates and the fraction of false positive lesions were calculated. RESULTS: Twenty-seven patients were treated with hepatic resection and/or RFA. Fourteen patients were treated with chemotherapy, 4 with Isolated Hepatic Perfusion (IHP) and 10 with systemic therapy. Based on the findings on CE-CT 31 patients were classified as surgical candidates and 10 as non-surgical patients. Based on the findings on CTAP, surgery should be the treatment of choice in 29 patients and 12 patients were classified non-surgical. CE-CT and CTAP disagreed in two cases (4.9%). Seventy-four metastases were identified at surgery and pathologically proved. CE-CT and CTAP showed 53 (.72) and 66 (.89) metastases, respectively. CONCLUSION: Despite a significantly higher detection rate for hepatic metastases, CTAP has no added value in the therapeutic stratification in candidates for resection of hepatic metastases of colorectal cancer.